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Recombinant Human Chorionic Gonadotropin But Not Dihydrotestosterone Alone Stimulates Osteoblastic Collagen Synthesis in Older Men with Partial Age-Related Androgen Deficiency

Bone Research Program (C.M., J.d.W.-M., M.J.S.) and Department of Andrology (P.Y.L., L.P.L., M.J., D.J.H.), ANZAC Research Institute, University of Sydney, Concord NSW 2139, Australia

Address all correspondence and requests for reprints to: Prof. Markus J. Seibel, M.D., Ph.D., FRACP, Bone Research Program, ANZAC Research Institute and Department of Endocrinology and Metabolism, The University of Sydney, Sydney NSW 2139, Australia. E-mail: mjs{at}anzac.edu.au.

Several randomized trials of androgen supplementation in older men have been undertaken. However, the relative contributions of testosterone (T) and estrogens on bone metabolism in aging men are controversial. Within the setting of two double-blind, placebo-controlled studies, we evaluated the effect of dihydrotestosterone (DHT) and recombinant human chorionic gonadotropin (rhCG) on bone turnover in healthy, community-dwelling older men with partial androgen deficiency (total T 15 nmol/liter). In the first study, 35 men (age 68.3 ± 6.8 yr; baseline T, 13.9 ± 3.3 nmol/liter) were randomized to receive either daily transdermal DHT (n = 17) or placebo for 3 months. In the second study, 40 men (age 67.4 ± 5.4 yr; baseline T, 11.4 ± 2.2 nmol/liter) were randomized to receive either rhCG sc (n = 20), two injections weekly, or placebo for 3 months. The following parameters were measured before, monthly during, and 1 month after treatment: serum T, estradiol (E2), and LH; markers of bone formation, serum amino-terminal propeptide of type I procollagen (S-PINP) and osteocalcin; markers of bone resorption, serum carboxyterminal cross-linked telopeptide of type I collagen and urinary deoxypyridinoline. Compared with placebo, treatment with DHT significantly increased serum DHT and suppressed LH and T levels, whereas E2 concentrations and markers of bone turnover did not change. In contrast, rhCG therapy significantly increased both T and E2, with the increases in E2 being supraphysiological. At the same time, rhCG significantly increased S-PINP concentrations with peak levels after 1 month (40%; P = 0.02 compared with placebo). In contrast, serum osteocalcin and carboxyterminal cross-linked telopeptide of type I collagen and urinary deoxypyridinoline levels did not change. The change in S-PINP levels correlated with the change in E2 levels (r = 0.59; P = 0.02) but not with a change in T.

We conclude that in older men with partial age-related androgen deficiency, rhCG treatment stimulates osteoblastic collagen formation proportionally to increased E2 concentrations but does not alter markers of mature osteoblastic function or bone resorption. In contrast, treatment with a pure, nonaromatizable androgen (DHT) has no effect on bone turnover despite a 20-fold increase in serum levels. Bone resorption was not accelerated during unchanged (DHT) or increased (rhCG) E2 levels, suggesting that minimal E2 levels are needed to maintain stable resorption, although direct androgen receptor-mediated effects cannot be excluded. If androgen supplementation is required for aging men, aromatizable androgens with sufficient endogenous estrogenic activity may have the most beneficial effects on bone.

C.M. is the recipient of a medical research fellowship from the Swiss National Science Foundation (No. 81BS-67544), and P.Y.L. was supported by fellowships from the National Health and Medical Research Council of Australia (ID 262025) and the Royal Australasian College of Physicians.

This work was presented in part at the 25th Annual Meeting of the American Society for Bone and Mineral Research, Minneapolis, Minnesota, 2003.

C.M. and P.Y.L. have contributed equally to this work.

Abbreviations: CV, Coefficient of variation; DHT, dihydrotestosterone; E2, estradiol; rhCG, recombinant human chorionic gonadotropin; S-BAP, serum bone-specific alkaline phosphatase; S-ICTP, serum C-terminal telopeptide of type I collagen; S-OC, serum osteocalcin; S-PINP, serum amino-terminal propeptide of type I procollagen; T, testosterone; U-DPD, urinary free deoxypyridinoline.

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